Background and purpose: Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. Experimental approach: Male rats received a 10-min infusion of 4 mg kg À1 of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg À1 morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. Key results: Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min À1 . The active efflux rate constant decreased from 0.0195 min À1 to 0.0113 min À1 in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (N max /V ecf ) of 0.66 ng min À1 ml À1 and was saturated at low concentrations of morphine (C 50 ¼ 9.9 ng ml À1 ). Conclusions and implications: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine.

Background and purpose: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. Experimental approach: Male rats received a 10-min infusion of morphine as 4 mg kg À1 , combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg À1 . EEG signals were recorded continuously and blood samples were collected. Key results: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k 1e ) was 0.038 min À1 , being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (k eo ) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal E max model. The values of the pharmacodynamic parameters E 0 , E max , EC 50 and Hill factor were 45.0 mV, 44.5 mV, 451 ng ml À1 and 2.3, respectively. Conclusions and implications: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations.

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